This program is addressed to the molecular biology, cellular biology and pathogenetic role of the multimolecular mediation systems of the blood and the interface of these systems with platelets, leukocytes and the endothelial surface of blood vessels. We propose to elucidate the mechanisms of activation and regulation of the coagulation sequence; the initiation of fibrinolytic pathways and their products; the influence of products of these pathways on the function of platelets, leukocytes and endothelial cells; the effects of endotoxins on platelets, the interactions of the coagulant and fibrinolytic pathways with the complement system; the structure and modes of action of vasoactive peptides produced by proteolytic activation of these pathways. We will analyze and integrate these molecular mechanisms in light of their effects on responsible cells and attempt to analyze the pathogenesis of hereditary and of acquired immunologic and infectious diseases of a vascular, hematologic and pulmonary nature. This includes study of the etiology and pathogenetic mechanisms in genetic and acquired bleeding disorders including hemophilia, atherosclerosis, immunologically mediated vasculitis, thrombosis, disseminated intravascular coagulation, and pulmonary vascular injury.